Genetic testing after sudden death with negative ancillary investigations: A French prospective study with...

In case of unexplained sudden death, learned societies recommend performing genetic testing on post-mortem biological specimens to search for a potential hereditary genetic cause and implement, with a multidisciplinary team, screening and prevention measures for the deceased's relatives. The aim of this study was to assess the diagnostic contribution of a rigorous multidisciplinary approach (combining autopsy, toxicology, anatomopathology and genetics) in case of unexplained sudden death.

This was a French, prospective (2008-2020), monocentric cohort study on unexplained sudden death in young subjects (aged 2-50 years). For each case, a rigorous autopsy, and the analysis of anatomopathological, toxicological, and genetic data were performed. Fresh cardiac and brain tissue samples were systematically collected and stored at -80°C. Genetic testing was performed using a targeted panel of 181 genes associated with channelopathies, cardiomyopathies and epilepsy. In negative cases, whole exome sequencing was performed. Exomes analyzed more than two years earlier were also reanalyzed.

One or two pathogenic or likely pathogenic (P/LP) variants were identified in 23.5 % (8/34) of patients, and positive toxicology results as well as notable microscopic cardiac anomalies were identified in 25 % (2/8) of them. One or two variants of uncertain significance (VUS) were identified in 35 % (12/34) of patients, of whom 50 % (6/12) had positive toxicology results and 58.3 % (7/12) showed microscopic cardiac anomalies. In addition, 2.9 % (1/34) of patients carried both a pathogenic variant and a VUS in another gene. The identified variants were associated with cardiac, neurological or metabolic disorders, or found in a gene of uncertain significance. Two patients carried pathogenic variants in genes with an uncertain association with sudden death. A total of 20 different genes carried variants of interest (VUS, P/LP variant): KCNH2, SCN5A, RYR2, SNTA1, PRKAG2, AKAP9, GDP1L, TECRL, TRDN, HCN4, ZFHX3, DEPDC5, TANC2, CHRNA2, DCHS1, DMD, EYA4, ACADM, KLF10, SCN7A.

Our study highlighted the value of extensive genetic testing in case of unexplained sudden death, reinforcing the importance of using a comprehensive, multidisciplinary approach. The presence of multiple genetic variants, minor anatomopathological changes and toxicological factors suggests the complex interplay of contributory mechanisms leading to death. Regular reanalysis of genetic data, combined with close collaboration between forensic pathologists, geneticists and clinicians, is essential to improve diagnostic yield and guide family management.